@article{10.1172/JCI142580, author = {Qian Zhang AND Larry D. Mesner AND Gina M. Calabrese AND Naomi Dirckx AND Zhu Li AND Angela Verardo AND Qian Yang AND Robert J. Tower AND Marie-Claude Faugere AND Charles R. Farber AND Thomas L. Clemens}, journal = {The Journal of Clinical Investigation}, publisher = {The American Society for Clinical Investigation}, title = {Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts}, year = {2021}, month = {4}, volume = {131}, url = {https://www.jci.org/articles/view/142580}, abstract = {Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.}, number = {7}, doi = {10.1172/JCI142580}, url = {https://doi.org/10.1172/JCI142580}, }